Genetic factors

Autoimmune diseases are diseases associated with dysfunction of the human immune system, which perceives its own tissues as alien and to damage them. Such diseases are called systemic, because, as a rule, is affected the whole system or even the entire body.

In the normal immune response develops only on foreign or modified self antigens. Aging and some diseases lead to the fact that there are antibodies and T-lymphocytes, directed against self-antigens — develop autoimmunity. A variety of clinical manifestations of autoimmune diseases is explained by differences in the localization, severity and mechanisms of damage of own tissues and organs. Autoimmune disease is a disease caused by autoantibodies (antibodies to self antigens) and cytotoxic T-lymphocytes directed against self-antigens. A clear link between the development of autoimmune diseases and the appearance of autoantibodies or cytotoxic T-lymphocytes to self antigens could not be detected always. For the diagnosis of autoimmune diseases using a variety of research.

Among the human diseases there are about 100 forms of diseases with autoimmune pathogenesis, while the number of autoimmune reactions and syndromes can reach several hundred. In addition, for a number of diseases, pathogenesis of which is not completely clear, such as schizophrenia, endometriosis, or amyotrophic lateral sclerosis there is a theory of autoimmune origin, which are based on some actual evidence, including the detection of autoantibodies.

Although autoimmune disease refers to rare diseases, however, according to various estimates, their total frequency of occurrence of leaves 20-25% of patients with General therapeutic pathology. In addition, common autoimmune diseases such as rheumatoid arthritis, diabetes type 1 diabetes, systemic rheumatic diseases, accelerate atherosclerosis and lead to cardiovascular disease.

Main part

Etiology of autoimmune disease

Genetic factors. Autoimmune phenomena tend to aggregate in certain families. For example, the first-degree relatives (siblings, parents and children) of patients with Hashimoto’s disease show a high incidence of thyroid autoantibodies and of overt and subclinical thyroiditis. Parallel studies have disclosed similar relationships in the families of pernicious anemia patients, in that gastric parietal cell antibodies are prevalent in the relatives who develop achlorhydria (absent or low hypochloric acid in gastric secretions) and atrophic gastritis.

Picture 1. The high incidence of thyroid and gastric autoantibodies in the first-degree relatives of patients with Hashimoto’s disease or pernicious anemia.

Many autoimmune diseases in humans and inbred animals are linked to particular MHC alleles. The association between human leukocyte antigen (HLA) alleles and autoimmune diseases in humans was recognized many years ago and was one of the first indications that T cells played an important role in these disorders (because the only known function of MHC molecules is to present peptide antigens to T cells). The incidence of a particular autoimmune disease often is greater among individuals who inherit a particular HLA allele(s) than in the general population. This increased incidence is called the odds ratio or relative risk of an HLA-disease association; the same nomenclature is applicable to the association of any gene with any disease. It is important to point out that although an HLA allele may increase the risk of developing a particular autoimmune disease, the HLA allele is not, by itself, the cause of the disease. In fact, the disease never develops in the vast majority of people who inherit an HLA allele that does confer increased risk of the disease. Despite the clear association of MHC alleles with several autoimmune diseases, how these alleles contribute to the development of the diseases remains unknown. Some hypotheses are that particular MHC alleles may be especially effective at presenting pathogenic self peptides to autoreactive T cells, or they are inefficient at displaying certain self antigens in the thymus, leading to defective negative selection of T cells.

Picture 17. Roles of non-MHC genes in autoimmunity

Hormonal influences. Whether or not one is of the XX or XY genotype has a profound effect on many aspects of life! This includes a general trend for autoimmune disease to occur more frequently in women than in men (Picture2) probably due, in essence, to differences in hormonal patterns. Indeed, collectively, 75% of autoimmune disease is found in females and most commonly arises during the childbearing years. The most striking gender bias is seen in SLE where, during this time of their life, women are 10 times more likely to develop this disease than men.

Picture 2. Increased incidence of autoimmune disease in females.

Pregnancy is often associated with amelioration of autoimmune disease severity, for example in rheumatoid arthritis (RA), and there is sometimes a striking relapse after giving birth, a time at which there are drastic changes in hormones such as prolactin, not forgetting the loss of the placenta. Certainly a general quietening down of immune responses in order to prevent immunological rejection of the fetus would be consistent with some degree of remission of an autoimmune disease during pregnancy. However, there needs to be a degree of caution in making any generalized statement here because some autoimmune diseases, such as lupus, can actually get worse during pregnancy.

Environmental impact. We usually measure the impact of environment using the twin studies. The external factors affecting to appearance of A.D.:

  1. What environmental agents can we identify? Well, diet could be one although there is scant evidence so far. Fish oils containing omega – 3 polyunsaturated fatty acids (PUFAs) have anti -inflammatory activity and, in some studies, have been shown to be beneficial for patients with RA. However, a recent meta -analysis (i.e. combining the results of several studies) concluded that much larger trials are needed before any firm conclusions can be reached regarding dietary influences in this disease. There is some evidence that iodine supplementation in iodine – deficient populations can lead to an increase in thyroid autoimmune disease.
  2. Although many autoimmune diseases have been linked in case reports to a wide range of drugs, the most firmly established example is drug – induced lupus. Procainamide and quinidine (both used to treat cardiac arrhythmia) and hydralazine (an antihypertensive drug) are most often implicated in this disease that shares many features with SLE, although the specificity of the anti – DNA tends to be towards the single – stranded form rather than double – stranded DNA (dsDNA) and patients tend to have more joint and less neurological and kidney involvement.
  3. Noninfectious environmental agents. Sunshine is an undisputed trigger of the skin lesions in SLE. Necrosis and apoptosis of keratinocytes resulting from the detrimental effects of sunlight leads to the release of nuclear autoantigens in the case of apoptosis these are associated with the cell surface blebs that characteristically appear in this type of cell death. Occupational exposure to a number of agents has been linked to the development of autoimmune disease. Particularly convincing associations are silica exposure with SLE, RA and scleroderma. Solvents have been implicated in, for example, multiple sclerosis, and pesticides with RA. Cigarette smoking increases the risk of RA and of Hashimoto ’ s and Graves ’ diseases.
  4. Clear – cut example in humans: acute rheumatic fever following infection with group A Streptococcus. In  3 – 4% of untreated patients, usually children, who develop a sore throat due to S. pyogenes infection there is a resulting polyarthritis, carditis and chorea (i.e. joint and heart inflammation together with involuntary movement). The link to the infection lies in the fact that the streptococcal M protein shares structural homology with cardiac myosin — a clear situation of molecular mimicry. Further complexity is injected by the knowledge that environmental microbes may sometimes protect against spontaneous autoimmune disease.


Pathogenesis of autoimmune disease

Autoimmune processes often lead to the development of the disease. Detection of autoantibodies for a particular disease indicates two possibilities:

  1. Autoantibodies are the cause of the pathological process (immunobiological control system depended). For example: mutations in the proliferating immunocytes, damage of optimal proportion of activity of quantity of T-suppressor/ T-helper, damage of optimal proportion of idiotype/ antiidotype, excess of costimulatory factors, etc;
  2. autoantibodies are formed due to tissue damage caused by one or another pathological process(immunobiological control system not depended), for example: damage of natural barriers, modification of our antigens, modification of genome due to viral infections, antigen mimicry;

Tissue damage in autoimmune diseases can occur through several mechanisms, which are analogous to three of the classical types of hypersensitivity reactions: type II (caused by autoantibodies reactive with cell surface or matrix antigens), type III (caused by immune complexes), and type IV (delayed-type  hypersensitivity, mediated by T cells).

  1. Type II Autoimmune Reactions(pic.3). Type II hypersensitivity reactions are caused by antibodies against altered self proteins, such as penicillin–protein conjugates. In the case of autoimmunity, antibodies generated against cell surface antigens/extracellular matrix proteins may be cytotoxic (type IIA) or they may have agonistic/antagonistic properties (type IIB). Examples: Graves’ Disease, Autoimmune Hemolytic Anemia.
  2. Type III Autoimmune Reactions(pic.4). Autoantibodies also cause disease by forming networks of autoantibodies bound to their antigens (immune complexes). The antigen-antibody complexes can deposit in tissues, causing inflammatory lesions. Serum sickness is manifested by fever, glomerulonephritis, vasculitis, urticaria, and arthritis, appearing seven to twenty-one days after primary immunization or two to four days after secondary immunization with a foreign protein.

Picture 3. Hypersensitivity Type II

Picture 4. Hypersensitivity Type III

Picture 5. Hypersensitivity Type IV

  1. Type IV Autoimmune Reactions (T-Cell Mediated)(pic5). Type IV hypersensitivity reactions are mediated by T cells that recognize peptides presented on the surface of antigenpresenting cells in the context of class II major histocompatibility complex (MHC) molecules and that produce the cytokines interferon γ(IFN-γ), interleukin 3 (IL-3), tumor necrosis factor (TNF) α, TNF-β, and granulocyte-macrophage colony-stimulating factor (GM-CSF). These cells constitute a subset of helper T cells termed TH1 cells. Elaboration of “TH1 cytokines” leads to macrophage recruitment and activation, enhanced expression of adhesion molecules, and increased production of monocytes by the bone marrow. Delayed type hypersensitivity in response to the intradermal injection of certain antigens, such as tuberculin (used for tuberculosis skin testing), is a classic example of a type IV hypersensitivity reaction. In the case of autoimmunity, self-antigens (instead of foreign antigens) plus MHC molecules are recognized by the antigen receptors of the TH1 cells. Examples of type IV autoimmune reactions include insulin-dependent diabetes mellitus (pancreatic antigens, such as glutamic acid dehydrogenase, insulin, and other islet cell antigens are recognized), multiple sclerosis (unidentified components of myelin are recognized), experimental antoimmune encephalomyelitis (an animal model of multiple sclerosis in which myelin basic protein (MBP) is recognized), and Hashimoto’s thyroiditis (thyroid antigens such as thyroid peroxidase and thyroglobulin are recognized).

Classification of autoimmune disease

  1. Depended on quantity of damaged tissue or organs may be “ organ – specific”  and  “nonorgan -specific. ”  (pic.6)

Picture 6. Spectrum of AUD


  1. Depended of dominant mechanism of development (Table 1)
1B-cellularHashimoto’s thyroiditis, hemolytic anemia, thrombocytopenia, leukopenia, systemic lupus erythematosus;
2T-cellularCertain types of polymyositis and Sjogren’s syndrome
3CooperativeSjogren’s syndrome, which is manifested by damages of the eye (dry keratoconjunctivitis) and mucous membranes of the mouth (xerostomia), scleroderma, dermatomyositis, polymyositis.

Table 1. Classification of AUD.

Depended on the damaged organ (Table 2):

Liverautoimmune chronic active hepatitis

primary biliary cirrhosis

Musclemyasthenia gravis
Bloodautoimmune hemolytic anemia

autoimmune leukopenia

autoimmune thrombocytopenia

Gastrointestinalatrophic gastritis of autoimmune type (leads to pernicious anemia)

ulcerative colitis (IBD-UC)

Crohn’s disease (IBD-C)

food protein intolerance enteropathies (such as gluten sensitive enteropathy [GSE, celiac disease, celiac sprue]

Nervous systemdemyelinating diseases (eg, multiple sclerosis), amyotrophic lateral sclerosis, sensor motor neuropathy

myasthenic syndromes:

3.    occular myasthenia

4.    myasthenia gravis

5.    Lambert-Easton paraneoplastic myasthenic syndrome

stiff person (stiff man) syndrome: antibody mediated chronic near total body cramp.

Guillain-Barre syndrome

Progressive multifocal leukoencephalopathy

paraneoplastic syndromes

transverse myelitis

Bickerstaff’s postinfectious brainstem encephalitis

KidneyGoodpasture’s syndrome

Immune complex glomerulonephritis (many different types, including poststreptococcal, cryoglobulin, DNA-anti-DNA in SLE, etc)

SkinPemphigus vulgaris

Bullous pemphigoid

Cicatricial pem

Dermatitis herpetiformis


Other autoimmune diseasesWegener’s granulomatosis

Spontaneous male infertility

Table 2. Classification of AUD by organs.

Clinical examples


This disease is a classic example of an autoimmune disease. It affects mainly women (over 90%) of childbearing age, although  can get sick children. The disease can occur in different ways, depending on the severity of the inflammatory process and which organs are damaged. It can take years. Sometimes there are long periods of remission. Usually, after menopause women are no outbreaks of the disease. Timely and properly diagnosed, to help control the disease in its early stages, can significantly extend the life of the patient.

Symptoms (pic-s. 7 and 8)

To symptoms of lupus erythematosus refers to a skin rash, especially in places exposed to light. The rash can be different: from mild redness to large blisters. In addition, there is pain in the joints, which sometimes swell and become deformed as a result of inflammation. Patients experience weakness. Inflammation in lupus can affect the heart and lungs; due to the accumulation of fluid in the lungs difficulty breathing. The Central nervous system accompanied by headache and even seizures. Many patients with systemic lupus erythematosus suffer from kidney damage. More than hurt the kidney, the worse the prognosis of the disease. In addition, lupus can cause destruction of red and white blood cells and platelets. This dramatically weakens the body’s immune defenses, making the patient vulnerable to infections prone to anemia, and the formation of bruises.

Picture 7. Symptoms of SLE                                            Picture 8. Butterfly rash

Signs of autoimmunity

Usually patients in the blood circulating various antibodies, including autoantibodies to DNA. Blood formed immune complexes of DNA with antibodies that are deposited in the tissues. This is the beginning of the chain of inflammatory events, leading to kidney damage. Overseeing the development of the disease is performed by measuring the level of antibodies to DNA and activity of complement in the blood (pic.9).

Picture 9. Laboratory test for SLE


Is an inflammatory disease that affects several systems of the body, but primarily attacks the small joints of the hands and feet. Can be damaged and large joints, including the elbow, shoulder, knee and hip. Inflammation affects the synovium of the joints that is responsible for lubrication. Lack of lubrication leads to pain and swelling of the joint. Women get rheumatoid arthritis two to three times more often than men. Rheumatoid arthritis you can get sick at any age, but the disease usually begins between the ages of 30 to 55 years. The disease can last for several years.


Onset may be sudden with simultaneous inflammation of many joints, but most joints are affected in turn. The severity of illness varies from relatively mild to very severe deformation of the joints, which is virtually untreatable. In most patients the disease has a persistent chronic course and leads to a gradual destruction of the joints and erosion of bone tissue.

One of the main signs of the disease is soreness of the joints. The other characteristic feature of the disease is thickening, as a rule, symmetrical. Develops joint stiffness, which is particularly concerned about patients in the morning when getting out of bed or after prolonged physical inactivity. Patients can experience fatigue and a feeling of General malaise.

Picture 10. Stages of RA

Other symptoms of rheumatoid arthritis include: weight loss, thinning skin with increased propensity to ulceration, dryness of mucous membranes of eyes and mouth, and sometimes inflammation of the peripheral nerves that causes numbness in the hands and feet. One of the very serious complications of the disease, which is quite rare, is the defeat of the first and second cervical vertebrae. Thickening of the vertebrae leading to compression of the spinal cord that can cause paralysis of upper and lower extremities. Surgical intervention can help prevent this serious complication (pic-s 10,11 and 12).


Picture 11. Hand of patient suffering RA           Picture12. Defeat of 1st and 2nd cervical v.

Signs of autoimmunity

In patients with rheumatoid arthritis in the blood circulating IgM antibodies, called rheumatoid factor, which are associated with other IgG antibodies. High levels of IgM detected not only in patients with rheumatoid arthritis, but also patients with other infectious diseases and malignant tumors. It is believed that the complexes of these antibodies are involved in the damage to the joints.


There are two forms of autoimmune thyroid disease: one of them is associated with excessive production of thyroid hormone (Graves ‘ disease) and the other with reduced production of the hormone (Hashimoto’s disease).

Low production of thyroxin Hashimoto’s disease leads to lethargy, dry skin and hair, the nerves of the limbs. Patients need throughout life to enter the thyroid hormone. In women, Hashimoto’s disease is found in 8 times more often than men, and onset usually occurs between the ages of 30 to 50 years. Often in the family history there are cases of dysfunction of the thyroid gland.  Graves’ disease caused increased production of thyroxin  and characterized by symptoms such as weight loss, irritability, trembling hands, increased heart rate. The hallmark of the disease is exophthalmia. In addition, patients not tolerate the heat and suffer from excessive sweating. The disease affects women 7 times more often than men, and usually begins after 40 years. This is the case in Graves’disease, which is due to the presence of antibodies to thyroid-stimulating hormone receptors (TSH-R) which act in the same manner as TSH.

Picture 13. Symptoms of  Hashimoto’s disease

Picture 14. Symptoms of Graves’ disease


  1. Control at the target organ level. The major approach to treatment, not unnaturally, involves manipulation of immunologic responses. However, in many organ-specific diseases, metabolic control is usually sufficient, for example thyroxine replacement in primary myxedema, insulin in juvenile diabetes, vitamin B12 in pernicious anemia and anti-thyroid drugs for Graves’ disease. Xenografts of genetically engineered fetal or neonatal pig tissue such as islet cells are under study, and stem cells are being differentiated in culture to produce a variety of tissues that could be used to replace destroyed tissues (pic.15).
  2. Anti-inflammatory drugs. Corticosteroids have long been used to treat autoimmune diseases as they not only suppress various aspects of the immune response but also control the inflammatory lesions and particularly the influx of neutrophils and other phagocytic cells. Patients with severe myasthenic symptoms respond well to high doses of steroids, and the same is true for serious cases of other autoimmune disorders such as SLE and immune complex nephritis. In RA, steroids are very effective and accelerate the induction of remission.
  3. Immunosuppressive drugs. Because it blocks cytokine secretion by T-cells, cyclosporin is an anti-inflammatory drug and, since cytokines like IL-2 are also obligatory for lymphocyte proliferation, cyclosporin is also an antimitotic drug. It is of proven efficacy in a variety of autoimmune diseases, as are the conventional nonspecific antimitotic agents such as azathioprine, cyclophosphamide and methotrexate, usually given in combination with steroids. The general immunosuppressive effect of these agents, however, places the patients at much greater risk from infections.
  4. Successful results have been obtained in a number of autoimmune diseases, especially when the treatment has been applied in combination with antimitotic drugs. However, plasma exchange to remove the abnormal antibodies and lower the rate of immune complex deposition in SLE provides only temporary benefit.
  5. T-cell control strategies (pic. 16)


Autoimmunity can be caused by defects or virtually any defects of the immune process. Believed that in the development of these diseases involves a variety of factors, including the immune system, genetic predisposition and environmental conditions.

Patients with autoimmune diseases such as rheumatoid arthritis found an increase in the number of cells of a special type (CD5). It is established that these b-cells produce antibodies that bind with DNA and form rheumatoid factors.

For the occurrence of autoimmune diseases has a value of excessive or insufficient production of other immune system cells, T-cells. T-cells-suppressor cells are involved in the recognition of “own” and “alien” and, thus, play an important role in the prevention of autoimmune diseases. There is evidence that patients with such diseases poorly functioning T cells-suppressors and the immune system is not able to regulate the immune response as “their” and “foreign” antigens. In people with autoimmune diseases, reduced number of suppressor T cells and their activity. However, the decrease in the function of T cells-suppressor sometimes also observed in healthy people, therefore, in the occurrence of diseases are involved, and other factors.

Believe that the increase in susceptibility to autoimmune diseases associated with excessive production of antigens, which is due to increased levels of T-cells another type of T cells-helper cells.

Hereditary defects of individual units of the complement system, involved in the dissolution of complexes antigen — antibody, can also contribute to the development of autoimmune diseases.

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Genetic factors

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